Abstract
BackgroundEvidence suggests that adenosine acts via cardiac A1 adenosine receptors (A1ARs) to protect embryos against hypoxia. During embryogenesis, A1ARs are the dominant regulator of heart rate, and A1AR activation reduces heart rate. Adenosine action is inhibited by caffeine, which is widely consumed during pregnancy. In this study, we tested the hypothesis that caffeine influences developing embryos by altering cardiac function.Methodology/Principal FindingsEffects of caffeine and adenosine receptor-selective antagonists on heart rate were studied in vitro using whole murine embryos at E9.5 and isolated hearts at E12.5. Embryos were examined in room air (21% O2) or hypoxic (2% O2) conditions. Hypoxia decreased heart rates of E9.5 embryos by 15.8% and in E12.5 isolated hearts by 27.1%. In room air, caffeine (200 µM) had no effect on E9.5 heart rates; however, caffeine increased heart rates at E12.5 by 37.7%. Caffeine abolished hypoxia-mediated bradycardia at E9.5 and blunted hypoxia-mediated bradycardia at E12.5. Real-time PCR analysis of RNA from isolated E9.5 and E12.5 hearts showed that A1AR and A2aAR genes were expressed at both ages. Treatment with adenosine receptor-selective antagonists revealed that SCH-58261 (A2aAR-specific antagonist) had no affects on heart function, whereas DPCPX (A1AR-specific antagonist) had effects similar to caffeine treatment at E9.5 and E12.5. At E12.5, embryonic hearts lacking A1AR expression (A1AR−/−) had elevated heart rates compared to A1AR+/− littermates, A1AR−/− heart rates failed to decrease to levels comparable to those of controls. Caffeine did not significantly affect heart rates of A1AR−/− embryos.Conclusions/SignificanceThese data show that caffeine alters embryonic cardiac function and disrupts the normal cardiac response to hypoxia through blockade of A1AR action. Our results raise concern for caffeine exposure during embryogenesis, particularly in pregnancies with increased risk of embryonic hypoxia.
Highlights
Mature and developing mammals modulate cardiac output through alteration of heart rate and cardiac contractility [1,2,3,4,5,6]
Evidence shows that adenosine acts via A1 adenosine receptors (A1ARs) to protect embryos from hypoxia [9,20]; the mechanisms by which A1ARs confer embryo protection remain poorly understood [9,20]
We investigated whether A1AR signaling modulates embryonic cardiac function, in responses to hypoxia
Summary
Mature and developing mammals modulate cardiac output through alteration of heart rate and cardiac contractility [1,2,3,4,5,6]. Heart rate changes play an important role in regulating cardiac output [1,2,3]. Factors that alter heart rate influence cardiac output and tissue perfusion in early development. Embryonic hypoxia [8,9] results in intrauterine growth restriction and reduced birth weight [10]. Hypoxia is an important part of the normal development process that drives proper outflow tract formation in the heart, as well as formation of embryonic vessels [11,12,13]. We tested the hypothesis that caffeine influences developing embryos by altering cardiac function
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